Exertional rhabdomyolysis (ER) is a common medical condition encountered by primary care and sports medicine providers that results from muscle tissue breaking down with exercise. ER can range in presentation from asymptomatic physiologic elevations of creatine kinase (CK) noted after exercise to severe metabolic complications, which may lead to acute kidney injury (AKI), acute compartment syndrome, and in rare instances, fatal arrhythmias (10,12,15,16,20). Although the majority of individuals with ER follow an unremarkable clinical course without any long-term sequelae or increased risk for recurrence, some may be left with residual morbidity. In addition, in a minority of those who develop ER, exercise may function as an “unmasker” for identifying those with myopathic conditions, which may place the individual at increased risk for future recurrence.
Currently no evidence-based guidelines exist to assist the provider in identifying those who may return safely to play or duty from those who are potentially at higher risk for a repeat event. In this manuscript, we describe two cases involving warfighters who presented to our facility with recurrent ER with need for further evaluation prior to permitting return to duty. We review the definition, epidemiology, etiology, and clinical course of ER and highlight “red flags” in the clinical presentation that may identify those at increased risk for recurrence. Most importantly, we introduce criteria for identifying the high-risk ER patient and a suggested algorithm to assist in evaluating underlying conditions that may lead to recurrence.
A 23-year-old Egyptian American male warfighter developed 4 episodes of ER, each was associated with decreasing levels of exertion over a 3-year period. He was active and healthy in high school and played soccer, volleyball, and basketball; his first episode of ER occurred after 1 d of intensive training during basic entry level military basic training. The next day, he developed severe muscle pain and limited motion and subsequently presented to the emergency department. He was treated as an outpatient with intravenous hydration and diagnosed with ER. His CK rose as high as 50,000 U·L−1 during his outpatient treatment and follow-up before he had full resolution of his elevated CK and symptoms of muscle pain and limited motion.
After this episode, he went on to complete basic training, including passing a physical fitness test without any further events. Eight months later, he had a second episode of ER with similar symptoms after a routine workout, and this time, he was hospitalized for aggressive fluid hydration. His CK with this episode rose to 18,000 U·L−1 before trending back down to normal. About two more years passed before his third episode of ER, which was triggered by a “routine” workout in which no increase in weights or new exercises were performed, he developed muscle pain and stiffness the day after the workout, which prompted him to present to his primary care physician. Given his prior ER and symptoms, a CK was drawn, which was elevated. He was admitted to the hospital for treatment and his CK peaked at over 13,000 before trending back to normal. Just 5 months later, he participated in 5 min of volleyball, followed by rest, and then only 5 more minutes of volleyball, which was previously a normal level of activity. Again, his CK rose to over 20,000 U·L−1, with even less exertion, which was accompanied by the familiar symptoms of muscle pain and limited motion. He was admitted to the hospital where he was treated for ER and referred to our facility for further assessment.
A 31-year-old African American male warfighter developed ER after participating in 35 min of CrossFit exercises. He awoke that evening with severe low back pain and had to crawl to the phone to call 911. He presented with “cola-colored” urine and an elevated CK and was admitted to a local hospital. During the hospitalization, he continued to experience muscular pain in his back and developed numbness in his right buttocks and posterior thigh. He was found to have a lumbar compartment syndrome, which required surgery for necrotic muscle in his lower back. After surgery, he fully recovered with no sign of previous neurovascular symptoms; his activity was to be limited to light exercise, and he was restricted from moderate or severe exercise. About a year later, he gradually returned to exercise. About 1 month after this gradual return to resuming exercise, his CK level was measured and found to be over 21,000 U·L−1. He was again restricted from activity, although his only other symptom was postworkout or morning dark urine. He was instructed to return to light exercise and a referral was placed for further evaluation.
A diagnosis of ER should be considered when symptoms of muscle soreness, stiffness, and weakness are out of proportion to the exercise performed and laboratory evidence of myonecrosis and release into the systemic circulation of muscle cell contents, including myoglobin, creatinine, CK, organic acids, potassium, aldolase, lactate dehydrogenase, and hydroxybutyrate dehydrogenase, is demonstrated (16,20). The skeletal muscle subtype CK-muscle is abundantly present and released as a result of skeletal muscle destruction. Serum levels exceeding 100,000 U·L−1 are not seen infrequently with ER and other instances of rhabdomyolysis. Because CK remains in the circulation longer than myoglobin and can be detected easily and efficiently, it is the most commonly used marker to diagnose rhabdomyolysis (16).
No universally accepted clinical case or laboratory definition of ER currently exists, but symptoms of muscle pain and stiffness out of proportion to what would be expected from exercise, along with CK elevations ranging from more than 5 times to more than 50 times the upper limits of normal, have been proposed (8,15,16,20). In a study done on military recruits at basic training in Fort Benning, GA, no specific CK level predicted the development of ER, AKI, or other complications, and it was proposed that ethnicity-specific values would be more appropriate than specific cutoffs (8). African American men and young athletic men have been demonstrated to have the highest baseline CK levels, and non-African American women have the lowest, thus gender, ethnicity, and physical fitness must be considered when using CK values for the diagnosis of rhabdomyolysis (8,10). In general, CK levels in excess of at least five times normal (depending on ethnicity), in combination with the appropriate clinical presentation, are accepted as evidence of muscle breakdown, which may be consistent with a diagnosis of ER.
Rhabdomyolysis is a breakdown of striated muscle fibers, termed myonecrosis, due to physical and nonphysical causes (10,15,16,20). Figure 1 depicts the sequence of events from injury to rhabdomyolysis. Physical causes may include compression, trauma, ischemia, electrical injury, hyperthermia, or excessive, prolonged, or repetitive exercise. Nonphysical causes may include alcohol, recreational and prescription drugs, other drugs and toxins, metabolic myopathies, infections, electrolyte imbalance, dietary supplements, and/or endocrinologic disorders (15,16,20).
Any one of these causes of cell injury can result in a decrease in intracellular adenosine triphosphate, which in turn leads to increased calcium in the sarcoplasm. As the calcium level increases in the sarcoplasm, the extracellular calcium decreases resulting in hypocalcemia. In addition, when myonecrosis occurs, myocyte intracellular contents — myoglobin, potassium, CK, free radicals and organic acids — are released into the circulation. Some of these substances are associated clearly with/responsible for the complications that may develop from rhabdomyolysis. Myoglobin can overload the kidney resulting in AKI while organic acids can lead to a metabolic acidosis. Potassium and other electrolyte abnormalities are responsible for cardiac dysrhythmias, whereas free radicals may lead to tissue edema resulting in compartment syndrome. If severe, any of these complications can progress to threaten both limb and life (10,12,15,16,20).
The incidence of ER is difficult to assess as no laboratory definition or clinical diagnostic criteria has been accepted universally. In one of the few published epidemiologic reports, approximately 26,000 hospitalized cases of rhabdomyolysis due to any cause were reported to be seen each year in the United States (16). In the military, acute ER occurs in 2% to 40% of individuals undergoing basic training, usually within the first 6 d. A recent review of ER cases in the U.S. military noted 402 episodes in 2012; a 30% increase was noted from 2008 to 2012 (16).
ER is seen commonly in the sports community, with several recent case reports published on athletes who sustained ER despite being physically fit. In one case, 12 high school football players in Oregon were hospitalized for ER after performing triceps exercises in a “football immersion camp” (17). Another group of football players in Maryland were hospitalized after performing a conditioning drill involving “triangulated pushups”; this led to one player requiring triceps fasciotomies as a result of the exertion (25). Another group of 41 division I swimmers at the University of South Carolina performed focused upper extremity exercises during a 3-d period, and this resulted in 7 of them developing ER requiring hospitalization (6). It is important to emphasize that all of these outbreaks involved novel exercises in a physically fit group of athletes.
ER is rhabdomyolysis associated with and possibly caused by excessive, prolonged, and/or repetitive exercise, particularly with significant eccentric involvement (12,15). Although low physical fitness is a risk factor, ER also can occur in fit individuals who perform exercises they may or may not be familiar with, as presented in the cases mentioned. Other variables that may increase the risk and/or severity of ER in select individuals include dehydration, sickle cell trait, exertional heat illness, extreme exercise training, and use of certain drugs such as diuretics or statins (22,23), several dietary supplements such as ephedra and high doses of caffeine (5,13), recreational drugs, or alcohol (2,16).
Exercise can serve additionally as a trigger to unmask underlying pathologies in previously asymptomatic individuals who are already at increased risk for developing ER. Although some degree of CK elevation will be seen in active individuals after intense or prolonged exercise, most ER cases are self-limited with no associated morbidity or long-term consequences. The few cases of ER that do go on to develop complications — such as AKI or when symptoms or laboratory abnormalities persist despite rest — provide suspicion for an underlying metabolic myopathy. Table 1 lists a variety of inherited or acquired causes of rhabdomyolysis that can predispose an individual to ER associated with exercise.
ER symptoms begin with muscle soreness, similar to other etiologies of rhabdomyolysis. Within the first 24 to 72 h, symptoms progress to severe muscle soreness, stiffness, swelling, and weakness that are involved also with significant limitations in range of motion (10,11,15,20). The classic triad of ER is muscle soreness, weakness, and dark urine. Although muscle soreness is anticipated after strenuous or new exercise, the muscle pain from ER is out of proportion to what one would expect normally. These symptoms, along with the presence of associated laboratory findings, confer the diagnosis of ER.
As noted previously, the laboratory results generally accepted to represent ER are a CK level five times higher than the upper limit of normal and a urinalysis positive for blood, without the presence of red blood cells (10–12,15,16). Importantly these laboratory findings must be coupled with an appropriate clinical presentation for the diagnosis of ER. The presence of “cola colored” or “tea colored” urine will accompany frequently these abnormalities due to the myoglobinuria; however this finding is not required for the diagnosis. Other abnormalities associated with pathophysiology of rhabdomyolysis, but not essential to the diagnosis, are, as previously described, hyperkalemia, hypocalcemia, an anion gap metabolic acidosis, and elevations in serum phosphorus, uric acid, myoglobin, and/or creatinine (2,16). Given the potential for electrolyte disturbances, an electrocardiogram should be considered early in the evaluation of ER.
Resolution of myoglobinuria usually occurs in 2 to 3 d, with clinical improvement of swelling and weakness within 1 to 2 wk (12). CK levels typically peak within 48 to 96 h followed by resolution within 10 to 14 d (8). If the clinician encounters a second spike of CK during hospitalization, a compartment syndrome may be present, which should be identified and treated appropriately (16). For those who respond appropriately to rest and hydration and do not develop any complications from ER, activity usually can be resumed at a low level upon resolution of symptoms with progression as tolerated.
An important outlier to the typical presentation of the warfighter or athlete with ER is the clinical case complicated by sickle cell trait. Although beyond the scope of this manuscript, these patients may present with a conscious collapse, such as a football player collapsing after serial wind sprints with his legs being unable to function. This exercise-associated collapse with sickle cell trait (ECAST) can be catastrophic with a fulminant rhabdomyolysis requiring the emergent attention of the clinical medical staff. Although exercise intensity, hydration, and environmental conditions have been associated with ECAST events, the precise etiology remains undetermined (14).
Currently no good laboratory marker exists for quantifying when one has recovered from rhabdomyolysis. Normalization of CK levels merely demonstrates that no further muscle damage is occurring and that the kidneys have cleared any substances resulting from or associated with muscle breakdown. Most clinicians would agree that an isolated case of ER, without certain risk factors (to be discussed below), would not necessitate further work-up. However some cases would be considered high risk for recurrence based on history and/or laboratory findings and would require further evaluation (10,15). An outline for return to physical activity after ER can be found at http://champ.usuhs.mil.
The High-Risk ER Patient
Currently no consensus guidelines exist for identifying the high-risk ER patient; however particular aspects of the history, physical examination, and laboratory values warrant further work-up.
The history and physical examination
Having had a previous episode of ER or heat injury is an obvious “red flag.” Even a history of recurrent muscle cramps or severe muscle pain following mild to moderate exercise, such that they interfere with activities of daily living, should prompt further work-up. Developing ER after a low to moderate workload also should raise suspicion of an underlying, predisposing factor, which may place the individual at risk for future recurrence or unusual complications from ER. Finally a personal or family history of malignant hyperthermia, unexplained complications, or death following general anesthesia, sickle cell disease or trait, or abnormal exertional muscle pains should all prompt further evaluation in an individual diagnosed with ER. Although not completely understood as previously discussed, persons with sickle cell trait who develop ER, exertional heat illness, and/or exercise-associated collapse warrant clinical scrutiny with prudent individualization (14).
The patient with recurrent ER requires a complete physical examination to look for clinical signs of an underlying myopathy. Specific parts of the physical that should not be missed are a neurologic examination including deep tendon reflexes and a full cranial nerve assessment, and a thorough musculoskeletal examination, which may reveal contractures, evidence of atrophy, or hypertrophy. Strength testing should be included to assess carefully for proximal or distal muscle weakness. A skin examination may clue the clinician in an underlying myopathy if characteristic skin rashes or lesions are present, such as Gottron papules or a heliotropic upper eyelid rash, which may be present in dermatomyositis.
Laboratory findings that should prompt further investigation include persistent CK elevation more than 5 times the upper limit of normal (after accounting for age, gender, and ethnic group), despite rest of at least 2 wk, markers of AKI that do not return to baseline within 2 wk, and a peak serum CK of >100,000 U·L−1. The CK level 100,000 U·L−1 as a cutoff is based on expert opinion and is meant to be overly conservative in order to include all individuals at a potentially higher risk of recurrence. These high-risk criteria are summarized in Table 2.
Although closer investigation of the cause of ER in an individual will necessitate further testing, certain clues from the history and physical and/or laboratory findings may indicate a specific cause. Table 3 provides the clinician with clinical history and physical and laboratory findings that raise suspicion to possible specific diagnoses.
A Proposed Algorithm for Evaluation
Evaluation of the patient at high risk can be challenging clinically, particularly in a resource-constrained environment. A suggested algorithm for evaluation of the high-risk patient is outlined in Figure 2. Once a patient has been identified as potentially high risk, the first step should be an appropriate consultation with an expert, such as a neuromuscular specialist. An Exercise Intolerance Mutation Profile, which screens for specific mutations in the genes that encode for carnitine palmitoyltransferase II, myophosphorylase, and myoadenylate deaminase, may be ordered, as this test involves only a simple blood draw rather than muscle biopsy. An alternative functional test that has been described to screen for suspected disorders of glycogenolysis/glycolysis and myoadenylate deaminase deficiency is the modified forearm ischemic exercise test (21). These tests again are ordered optimally in consultation with a neuromuscular specialist. In our clinical setting, which often requires extended travel, we have found utility in ordering these tests after a verbal consultation and before arranging for a formal in-person consultation with a neuromuscular expert.
Working through this algorithm, if the Exercise Intolerance Mutation Profile is negative, then other risk factors, clinical clues, or causes of increased susceptibility to developing ER may dictate or prompt further testing. Electromyography may assist with diagnosis of myopathic causes of ER, whereas heat tolerance testing, which involves controlled exposure to an exercise heat stress, will assess an individual’s heat susceptibility. Because exertional heat illness can predispose an individual to developing ER, it is important to rule out heat susceptibility as a possible cause for ER. A caffeine-halothane contracture test (CHCT) is the gold standard for diagnosis of malignant hyperthermia susceptibility, and an association between ER and malignant hyperthermia has been cited multiple times in the literature (1,3,4,7,9,18,19,24). More information regarding malignant hypothermia can be found at www.mhaus.org.
A muscle biopsy with a myoglobinuria panel would test for disorders such as McArdle disease, Tarui disease, phosphoglycerate kinase deficiency, phosphoglycerate mutase deficiency, lactate dehydrogenase deficiency, phosphorylase A+ total deficiency, phosphorylase b kinase deficiency, carnitine palmitoyltransferase II deficiency, and myoadenylate deaminase deficiency. Any one of these deficiencies noted in the myoglobinuria panel might increase an individual’s risk for developing ER. We recommend using a Clinical Laboratory Improvement Amendments approved laboratory, such as Guthrie Laboratory, where these genetic analysis tests can be ordered.
Following the algorithm we have outlined can lead to a specific diagnosis, and appropriate interventions for treatment with risk mitigation strategies can be implemented. In many cases, however, an extensive work-up will not yield a specific diagnosis. In these scenarios, return to play or duty decisions can be difficult and should be made in conjunction with the appropriate specialist.
Case 1 follow-up
Detailed work-up of the two warfighters with recurrent ER confirmed a different etiology in each case. Both cases are good examples of the need to identify and treat warfighters with ER before they develop serious morbidity or even life-threatening events. This is especially true of case 1 who had 4 episodes of ER each with significant elevations of serum CK over a 3-year period before he was referred for definitive evaluation by a neurologist. Specialized testing that included an exercise intolerance panel, histology and histochemistry, muscle biopsy, myoglobinuria panel, and CHCT was then performed. Most of the tests were not informative, except for a positive CHCT.
As previously mentioned, a link between ER and malignant hyperthermia has been described in a number of cases (1,3,4,7,9,16,18,24) and is seen in this example as well. This diagnosis places him at higher risk for future occurrences of ER. Follow-up molecular testing for causative mutations in the RYR1 gene would be helpful in approximately 70% of cases for further testing and genetic counseling of family members especially since this is an autosomal dominantly inherited disorder.
Case 2 follow-up
Case 2 was sent to a sports medicine provider after his second episode of ER for further evaluation. A sickle cell screen was ordered and case 2 was found to be positive for sickle cell trait, which would place this patient in the high-risk category. When considered high-risk ER, it is recommended that the clinician consult a regional or national expert in myopathic disorders to further evaluate or test prior to allowing the individual to resume any moderate- or high-intensity exertion (14). After further testing and specialty consultations, case 2 underwent a muscle biopsy, which was CHCT negative; however results revealed a phosphofructokinase deficiency, which is associated with ER. Having phosphofructokinase deficiency, in combination with sickle cell trait, ultimately places case 2 at risk for future episodes of ER and its associated complications.
Most patients who develop ER will have none of the high-risk factors identified and may return gradually to normal activity after proper treatment and clinical recovery. Nevertheless some cases may result from inherent predisposition, as outlined in the cases mentioned, and it is essential for clinicians to be aware of the high-risk criteria to evaluate and refer properly such patients with ER. Lack of appropriate management in these high-risk cases can compromise potentially the patient in danger of recurrent ER episodes, with all their attendant complications, and most importantly, further delay identification of the underlying/predisposing cause(s). Having a more comprehensive knowledge of those who may be at higher risk will help us prevent a likely recurrence and the potential life-threatening complications of ER. Moreover being able to identify those high-risk cases also may assist in the classification of low-risk cases and save unnecessary referrals, diagnostic tests, missing training days, etc. This also will expedite return to duty/play with more confidence.
The authors declare no conflicts of interest and do not have any financial disclosures.
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